Therapeutic composition containing 2-amino-oxazolin-4-one derivatives

ABSTRACT

A THERAPEUTIC COMPOSITION FOR THE TREATMENT OF PATIENTS REQUIRING AN ANTI-INFLAMMATORY, ANTI-PYRETIC OR ANALGESIC AGENT COMPRISES A PHARMACEUTICALLY ACCEPTABLE CARRIER AND FROM ABOUT 5 MG. TO ABOUT 1 G. OF A DERIVATIVE OF 2-AMINO-OXAZOLIN-4-ONE IN WHICH THE SUBSTITUENT IN THE 5-POSITION MAY BE ALKYL OF 1-14 CARBON ATOMS, PHENYL, HALOPHENYL, LOWER ALKOXYPHENYL OR METHYLENE-DIOXYPHENYL, THE AMINO NITROGEN BEING A PART OF A PIPERIDINE, PYRROLIDINE, MORPHOLINE OR PIPERAZINE RING, WHICH RING MAY ALSO CONTAIN A C-LOWER ALKYL OR C-DI-LOWER ALKYL SUBSTITUENT, AND WHEN THE RING ISPIPERAZINE, THERE MAY BE SUBSTITUTED ON THE SECOND NITROGEN ATOM THEREOF AN ALKYL, HYDROXYALKYL, N-DIALKYLAMINOALKYL, PHENYL, HALOPHENYL, ALKYLPHENYL, ALKOXYPHENYL, BENZYL, ALKANOYL, BENZOYL, HALOBENZOYLALKYL, OR TRIALKOXYBENZOYL GROUP.

United States Patent 3,567,826 THERAPEUTIC COMPOSITION CONTAININGZ-AMINO-OXAZOLIN-I-ONE DERIVATIVES Jan Marcel Didier Aron-Samuel, 118Rue Carnot, 92 Suresnes, Hauts-de-Seine, France N0 Drawing. Filed May 2,1966, Ser. No. 546,542 Claims priority, application Great Britain, May10, 1965, 19,674/ 65 Int. Cl. A61u 27/00 US. Cl. 424-250 7 ClaimsABSTRACT or THE DISCLOSURE A therapeutic composition for the treatmentof patients requiring an anti-inflammatory, anti-pyretic or analgesicagent comprises a pharmaceutically acceptable carrier and from about mg.to about 1 g. of a derivative of 2amino-oxazolin-4-one in which thesubstituent in the 5-position may be alkyl of 1-14 carbon atoms, phenyl,halophenyl, lower alkoxyphenyl or methylene-dioxyphenyl, the aminonitrogen being a part of a piperidine, pyrrolidine, morpholine orpiperazine ring, which ring may also contain a C-lower alkyl orC-di-lower alkyl substituent, and when the ring is piperazine, there maybe substituted on the second nitrogen atom thereof an alkyl,hydroxyalkyl, N-dialkylaminoalkyl, phenyl, halophenyl, alkylphenyl,alkoxyphenyl, benzyl, alkanoyl, benzoyl, halobenzoylalkyl, ortrialkoxybenzoyl group.

The present invention concerns a therapeutic composition exhibiting, inparticular, anti-inflammatory, antipyretic and analgesic properties.

This composition is characterized in that it contains, as activeprinciple, in association with a pharmaceutically acceptable vehicle, a2-amino-oxazolin-4-one derivative of general formula:

N A Ri wherein R is an alkyl group or a substituted or unsubstitutedphenyl group, A is a piperidino, pyrrolidino, morpholino or piperazinoring, each of said rings possibly comprising one or two lower alkylsubstituents on nuclear carbons, and R when A is a piperazino ring, is asubstituent of the second nitrogen atom of said ring, consisting ofhydrogen, an alkyl, acyl, aryl, alkaryl or aralkyl group, said groupsbeing substituted or unsubstituted, or an acid addition salt of such aderivative with a pharmaceutically acceptable acid.

The preferred meanings of R and R are the following:

R=alkyl group having ll4 carbon atoms, phenyl and phenyl monoordi-substituted with halogens, alkoxy groups or a methylene-dioxy group;

R =hydrogen, alkyl, hydroxyalkyl, N-dialkyl substituted alkylamino,phenyl, halophenyl, alkylphenyl, alkoxy phenyl, benzyl, alkanoyl,benzoyl and trialkoxybenzoyl, the alkyl, alkoxy and alkanoyl groups inthis list being lower groups having 1-6 carbon atoms.

Derivatives (I) are, as a whole, novel derivatives, also contemplated assuch according to the invention, to the exclusion of three of themwherein R is the phenyl group and A is the piperidino, piperazino (withR =methyl) and morpholino ring, respectively.

The latter three compounds are described by Charles F. Howell et al. inan article published in Journal of 3,567,826 Patented Mar. 2, 1971Organic Chemistry (1962, vol. 27, pages l6791685), although they are notdisclosed as therapeutically active.

Indeed, the anti-inflammatory, anti-pyretic and analgesic properties ofderivatives (I) as a whole and, consequently, of the latter threecompoundsdiscovered according to the inventionwere found to be mostimportant and insure to these derivatives wide applicability inmedicine, particularly for the treatment of rheumatism. Said propertiesare all the more unexpected since other previously described derivativesof Z-amino oxazolin-4- one not comprised within the scope of generalFormula I and some of which are also mentioned in the paper by CharlesF. Howell et al. mentioned above were all suggested as psychotoniccompounds.

In contrast, derivatives (I) are devoid of any psychic effect, theirproperties, as mentioned above, being effective in an entirely differentfield.

As will be seen hereinafter in more detail, these prop erties areaccompanied by low toxicity, the new derivatives possessing a broadtherapeutic safety range and avoiding to a large extent the drawbacks ofallergy or gastric irritation which restrict the utilization of theproducts at present in use (such as corticoids or phenylbutazone).

To prepare the new derivatives (I), a compound of general formulanamely, a Z-amino, oxaZolin-4-one substituted at the 5- position withradical R, is reacted with a heterocyclic base of general formula R, Aand R having the above defined meanings, the possible substituent Rbeing, if desired, hydrogen and replaced, after the reaction, by anotherdesired radical included within the meaning of R The reaction betweenthe Z-amino oxazolin-4-one and the heterocyclic base may be etfected invarious Ways.

According to one embodiment, one mole of the former reagent is heatedwith an excess (5l0 moles) of the latter reagent, the heating time beingvariable (generally between 4 hour and 3 hours).

The desired product crystallizes upon cooling and the possible additionof a non-polar solvent. It may then be recrystallized from a suitablesolvent.

The same procedure can be used without heating, however with a longerreaction time (6-24 hours). As a modification, the reaction can becarried out by heating in the presence of a solvent such as isoamylalcohol or Xylene. According to this latter modification, using anexcess of solvent, the amount of heterocyclic base used may be reducedand it is possible to operate with substantially equimolar amounts ofZ-amino oxazolin-4-one and heterocyclic base.

When R in the resultant compound, is hydrogen, and when it is desired toreplace this hydrogen with another R substituent, this compound may beheated in a solvent such as benzene with an halide of this substituent,in the presence of an acid binding agent such as triethylamine.

The substituted Z-amino oxazolin-4-ones (II) are novel compounds whenradical R is an alkyl group having 4 or more carbon atoms.

For the preparation thereof, an a-hydroxyester of formula wherein R hasthe above meaning and R is a lower alkyl group, is reacted withguanidine. The reaction is advantageously effected by heating thereagents within a solvent such as alcohol, according to the examplegiven below.

Preparation of compounds (II): 2-amino-5-butyl oxazolin-4-one 2-amino-isobutyl oxazolin-4-one (203 C.), 2-amino 5-hexyl oxazolin-4-one (214C.), 2-amino S-nonyl oxazolin-4-one (l98200 C.), 2-amino S-tetradecyloxazolin-4-0ne (180182 C.).

The following examples illustrate the preparation of some of thederivatives (I):

EXAMPLE 1 2-pyrrolidinyl S-phenyl oxazolin-4-one or LA 1126 To 35.2 g.(0.2 mol) of S-phenyl Z-amino oxazo1in-4- one are added 81 g. ofpyrrolidine (1.24 mol). The mixture is refluxed gently during 1% hours.A solid crystallizes upon cooling.

After recrystallizations, 24 g. of LA 1126, M.P. 150- 152 C. (yield 52%)are obtained.

EXAMPLE 2 2-piperidinyl 5-phenyl oxazolin-4-one or LA 1123 To g. of5-phenyl 2-amino oxazolin-4-one are added 24 g. of piperidine. Themixture is stirred in the cold during 24 hours. The white slurry isfiltered by suction.

There are obtained 13 g. of LA 1123, M.P. 125 C. (yield above 90%).

EXAMPLE 3 2-piperazinyl S-phenyl oxazolin-4-one or LA 1148 To 8.8 g.(0.05 mol) of S-phenyl Z-amino oxazolin-4- one are added 21.5 g. (0.25mol) of anhydrous piperazinc and 100 ml. of xylene.

The mixture is refluxed for 1% hours.

After cooling, the reaction mixture is suction filtered and theinsoluble is recrystallized from 100 ml. of benzene.

There are obtained 7 g. of LA 1148, M.P. 146-148 C., with a yield of51%.

EXAMPLE 4 Z-N-methylpiperazinyl S-phenyl oxazolin-4- one or LA 1124 To17.6 g. of S-phenyl 2-amino oxazolin-4-one (0.1 mol) are added 11 g.(0.1 mol) of N-methylpiperazine and 100 ml. of anhydrous xylene. Themixture is heated by means of an electric heating flask. NH is evolvedat about 110-120 C.

After refluxing for 2 hours (138 C.) the reaction is complete anddissolution is complete. Heating is con- 4 tinued for another /2 hourand is then filtered hot. Crystallization occurs on cooling. The mixtureis washed with xylene, followed by cyclohexane. There are obtained 24 g.of creamy white product M.P.=148150 C. (yield: 93

EXAMPLE 5 2-[4'-( 3 .4".5"-trimethoxy benzoyl) ]-piperazinyl5-phenyl-oxazolin-4-one or LA 1149 To 12.3 g. of 2-piperazino 5-phenyloxazolin-4-one (0.05 mol) are added 5 g. of anhydrous triethylamine 0nKOH (0.05 mol) and ml. of benzene. The mixture is stirred, and in theresultant suspension is poured, over 5 minutes, a solution of 11.5 g. of3.4.5.-trimethoxy benzoic acid chloride (0.05 mol) in 75 ml. of benzene.The mixture is refluxed for 1 hour.

The resultant product is recrystallized from ml. of dimethyl formamide.

There are obtained 18.1 g. of LA 1149 (yield, 83%); M.P.=250252 C.

EXAMPLE 6 5-butyl-2-piperidino-oxazolin-4-one or LA 1190 To 6 g. of2-amino-5-butyl-oxazolin-4-one are added 38 ml. of piperidine and themixture is refluxed for twenty minutes. The mixture is brought todryness under a pressure of 20 mm. The resultant oil is taken up with 25ml. of ether and a mixture of hydrochloric acid and ether is added tothis mixture to pH 1. There are thus obtained 8.5 g. of 5-butylZ-piperidino oxazolin-4-one hydrochloride (yield, 85

The product obtained has a Kofler melting point of 134-136 C.

Analysis.N% lO.72 (theory 10.74). C1%=13.48 (theory 13.60).

EXAMPLE 7 S-hexyl 2-piperidino oxazolin-4-one or LA 1195 Using the sameconditions as in Example 6, from 2- amino S-hexyl oxazolin-4-one, thereis obtained a clear oil at laboratory temperature which, however,crystallizes on cooling to 0 C. The hydrochloride is obtained byaddition of hydrochloric acid in isopropanol to the ether solution ofthis base (yield, 83%).

The Kofler melting point of 5-hexyl Z-piperidino oxazolin-4-onehydrochloride is 124-126 C.

Analysis.Cl%=12.27% (theory 12.28).

EXAMPLE 8 5-hexyl Z-N-butylpiperazino oxazolin-4-one or LA 1167 To 7.1g. of N-butylpiperazine and 50 ml. of xylene there are added 9.4 g. ofZ-amino S-hexyl oxazolin-4- one. The mixture is refluxed for 1 hour andis evaporated in vacuo. The oily residue is taken up with 50 ml. ofacetonitrile. The insoluble is filtered. The resultant oils is broughtto dryness and is taken up with 50 ml. petroleum ether. 5-heXyl2-N-butylpiperazino oxazolin-4-one crystallizes as needles (yield: 49%).

Analysis.-N%'=13.45 (theory 13.58).

The Kofier melting point of the product obtained is 48-50 C.

EXAMPLE 9 S-hexyl Z-N-methylpiperazino oxazolin-4-one or LA 1197 Usingthe same conditions as in Example 8, from 2- amino 5-hexyloxazolin-4-one and N-methylpiperazine there is obtained S-hexylZ-N-methylpiperazino oxazolin- 4-one (yield 53) having a melting pointof 40 C. (Tottoli).

Analysis.--N% =l5.78 (theory 15.72).

This base, treated with the equivalent of hydrochloric acid inisopropanol gives S-hexyl Z-N-methylpiperazino oxazolin-4-onehydrochloride having a melting point of 208 C. (Tottoli).

6 Anaylsis.-C1%=11.63 (theory 11.67). N%=13.95 ketone is5-butyl-2-N-(hydroxyethyl)-piperazino oxazol- (theory 13.83). in-4-one(yield, 41%

EXAMPLE H'Ih product obtained has a Kofler melting point of S-butyl2-morpholino oxazolin-4-one or LA 1184 r Analy is N%:15.57 (theory15.58). To 9.6 g. of morpholine and 150 ml. of xylene there are added15.6 g. of 2-amino S-butyl oxazolin-4-one. EXAMPLE 12 The mixture isrefluxed for 2 hours. The solid obtained 5- 1 2-N-(paratolylypiperazino1 4- on cooling is filtered and recrystallized from acetonitrile. or LA1182 There is obtained S-butyl 2-morpholino oxazolin-4-one 10 (yield40%). Using the same conditions as in Example 11, from The productobtained has a Kofler melting point of Z-amino S-butyl oxazolin-4-oneand N-(paratolyl)-piper- 90 C. azine there is obtained S-butyl2-N-(paratolyl)-piperazino Analysis.-N% =12.46 (theory 12.47).oxazolin-4-one.

The product obtained has a Kofler melting point of EXAMPLE 11 C.

Analysis.N%=l3.24 (theory 13.32). Sbutyl zi gg f fgg oxazohn 4 one Inthe table below are listed derivatives (I) prepared according to theabove examples and other derivatives To 14.3 g. ofN-(hydroxyethyl)-piperazine and 150 (I) prepared according to similarprocedures.

Melting point,

Code No. R 1 0- LA 1108 Isobutyl Piperidino. 66-66 LA 1109 HexyL4-methyl plperidlno, H01. 138-140 Pyrrolidino, HCL 1 153 Pyrrolidino. t101 N(p.tolyl)piperazino- 132 N(hydroXyethyD-piperaz1no 86N-methylpiperazino, HCL 258-260 Iiperidino 125 N-rnethylpiperazinm-148-150 N-pheny1piperazino 190-192 Pyrrolidino 152 N-paratolylpiperazin0.1 180 Morpholino 164-166 y1 N-methylpiperazino, HCl- 243 p-Fluorophenyl4 N-methylpiperazinm.-. 156

Phenyl N-benzylpiperazino. 162-164 p-bromophenyl N -methy1piperazino.182-184 Phenyl N-(hydroxyethyl) piperazmm 90-92 N-(paramethoxyphenyl)piperazmo. 182-184 do N-(parachlorophenyl)piperazino156-158 p-Methoxyphenyl Piperidino 108-110 o-Chlorophenyl 110 T 1 98-1003,4-methylene dioxyph enyl Pyrrolldmo. 152-1 54 Phenyl 4-n1ethylpiperldmo 104-106 do 3-methyl piperidino..- 136-138 Methyl. Piperidino t48-50 Pheny1 Piperazinoqh 146-148 do [4 (3"- 4-5-benzoy1)] piperazino250-252 p-Chlorophenyl Piperldino 118-120 p-Bromophenyl do 138-140Phenyl N-acetylpiperazino. 142-144 p-Bromophenyl Morpholino 180-182p-Chloropheny] N-p. tolylpiperazino. 202-204 PhenylN-diethylaminoethylpiperazino 84-86 3-1nethy1 N-aeetylpiperazino-162-164 3.5-dimethyl N-acetyl piperazino. 180-100 N-propylpiperazinor134-136 N-butylpiperazin0 112-114 Piperidiuo, HCL 124-126 N-butylpiperazino 48-50 N-propylpiperazino- 44-45 Piperazin0N-diethylaminoethylpiperazino 1 -36 N-(4-chlorobutyrophenone piperazino152-154 N-4-fluorobutyroph enone-4-y1) pip erazi 134-136 N-(p.to1yl)piperazino 139 N-(hydroxyethyl)-piperazino 71 Morpholino 00Piperidino 64-66 N-methylpiperazln 74-76 Piperidino N-methylpiperaz54-56 Plperldmo, HCl 134-136 Piperidino," 98-100 Piperidino, H 124-126N-meth 1 216-217 N-methylpiperazino, base. 1 56-57 N-methylpiperazino,HCL I 208 N-methylpiperazino, base. .1 1 40 N-propylpiperazino 64-66N-phenylpiperazino 118 ml. of xylene there are added 15.6 g. of2-amino-5-butyl 7 Derivatives (I) were submitted to a pharmacologicaloXaz0lin-4-one. The mixture is refluxed for 1% hours and study for thepurpose of evaluating their toxicity and i evaporated under 20 Th il idi t k properties. The results of these tests are summarized up withacetonitrile (200 ml.) and the insoluble is 111- below:

tered. On evaporation, there is obtained an oil which TOXICITYcrystallizes. The solid recrystallized from methyl ethyl 75 (a) Acutetoxicity: The LD of all derivatives (I) Other experiments were carriedout by including under the skin of the rat a piece of cotton wool whichcreated a local inflammatory granuloma. After days, the granuis high, asmay be seen from the following values obtained orally in mice:

Determined by intravenous perfusion at 1% in guineapig, the toxicity isalso very low. As an example, the lethal dose was found to be 240mg./kg. with LA 1197 on uninterrupted perfusion and of 420 mg./kg. wheninterrupting and subsequently resuming perfusion.

(b) Chronic toxicity: This was studied in rat and dog during four monthswith compounds LA 1123, 1124, 1195, 1196 and 1197, at a daily dosage of-300 mg./kg. and no significant anomaly was noted in the blood picture,in renal and hepatic tests and in the tests of the various organsaffected during the pathological examination, and neither was therenoted any unfavorable influence on the growth of the animals.

(2) ANTI-INFLAMMATORY EFFECT This was studied in a systematic manner byinjecting in the paw of the rat 0.2 ml. of a polyvinyl pyrrolidonesolution or of some other irritant material such as 9. formaldehydesolution, a 10% Teepol solution or a carrageenin solution. This createdan edema of the paw. The diameter of the latter is measured with amicrometer caliper and by plethsmorgraphy before and after injection, at/2 hour intervals over a period of 3 hours:

(a) on reference rats,

(b) on rats subjected to the drug to be tested,

(c) on rats subjected to a known powerful anti-inflammatory agent usedfor comparison purposes, namely phenylbutazone.

'Product: LD 50 LA 1108 About 1000 Ink/kg loma 1s removed and we1ghedcompara t1vely in respect LA 1109 About 1400 5 of the reference anlmals,the animals which had absorbed LA 1110 About 1250 mg/kg' the product tobe tested and the rats submitted to cortisone LA 1112 800 mg./ kg.treatment L A 1114 1500 mgjkg The result of these tests s summarized inthe follow- LA 1116 About 1500 mg /kg mg table in which the efliciencyof each product is ex- LA 1117 200) Ina/kg. 10 pressed as a percentageof the reduction of the edema LA 1123 600 mg/kg. relative to thereference animals: LA 1124 350 mg./ kg., and 380 mg./kg.

orally in rat. D P

i: Product rug/ i1 3: r c lil tio it LA 1127 4 g./kg. 3 Q LA 1128 3.5g./kg. 5 25 LA 1130 450 mg./kg. 5 53 LA 1131 4 g./kg. 0.1 LA 1134 6,50mg./kg. 53 LA 1135 4 g./kg. 50 07 LA 1137 s50 mg./kg. g g; LA 1138 3g./kg. 50 37 LA 1139 4 g./kg. g 33 LA 1145 1 g./kg. 5 20 LA 1146 1.2g./kg. g 2; LA 1147 2.25 g./kg. 5 20 LA 1148 11s mg./kg. g g3 LA 1149 4g./kg. 5 25 LA 1150 3500 mglkg. g3 LA 1151 4 g./kg. 0.1 LA 1181 800mg./kg. LA 1182 1500 mg./kg. LA 1183 300 mg/kg It is clear that this isa general property common to all LA 1184 1500 mg./kg. members of thefamily. To g1ve an idea of its intensity, it LA 1185 800 mgjkg. will bementioned that 50 mg. of LA 1123, for example, LA 1186 800 mg/kg. aretwice as effective as 200 of phenylbutazone, that is, an LA 1187 800mgjkg action eight times stronger than that of one of the most LA 1188800 mg/kg powerful known anti mfiammatory agents, with a much LA 1190520 mgjkg Wldel tolerance margin. LA 1193 600 mg'/kg Derivatives (I)such as LA 1190, 1198, 1197, 1196 and LA 1 5 4 lug/kg. 1182 have shownantl-mflammatory properties t do f LA 119 5 mg/kg less than 1 mg./kg.and are thus active at doses that are LA 11 ,5 much lower than theactivity doses of products widely LA 9 40 used clmlcally such asdehydrocortisone, A-cortisone and LA 1199 800 mg./kg. phenylbutazone.

3 ANALGESIC EFFECT This was studied by measuring the time that miceplaced on a plate maintained at 56 C. took to start to lock their paws.The product is examined comparatively with a reference analgesic,generally codeine hydrochloride as a subcutaneous 10 mg./ kg. injection.The test product is administered orally at the dose of mg./ kg.

The results given in the following table are expressed as a percentageof the slowing down of the paw licking time:

To give an idea of the intensity of this effect, it will be noted that12 mg. of LA 1124 administered orally are as eifective as mg. ofmorphine hydrochloride administered by the subcutaneous route.

(4) AN TI-PYR-ETIC ACTION This action was investigated in rabbit, byantagonism with respect to fever caused by injection of T.A.B. vaccine.

In particular, ingestion of 100 mg. of LA 1195 or LA 1197 causes a rapiddecrease of the temperature of the animal to which T.A.B. vaccine hasbeen injected previously, whereas this temperature remains high in thecontrols. In contrast, no temperature lowering effect is noted in thenormal animal.

(5 STIMULATING EFFECT None of compounds (1) causes a stimulating effecton the central nervous system of mice when tested according toconventional methods.

In human clinics, derivatives (1) together with their pharmaceuticallyacceptable salts, due to their excellent anti-inflammatory, analgesicand anti-pyretic properties, are useful especially in the treatment ofrheumatism and also in the treatment of neuralgia, headaches and,generally, of all conditions wherein there exists an inflammatory orpainful syndrome. v

In such indications, derivatives (I) and the salts thereof areformulated as therapeutic compositions with the usual pharmaceuticalvehicles for oral, rectal or parenteral administration.

Thus, for oral administration, derivatives (I) and the salts thereof maybe formulated, for example, in the form of tablets, granules, capsules,potable syrups and solutions, the vehicle, in the two last-named cases,consisting of a flavoured liquid. It may sometimes be useful to providethe tablets with an enteric coating to prevent any risk of destructionof the active principle in the stomach.

For rectal administration, derivatives (1) and the salts thereof may beformulated in the form of suppositories with conventional pasty vehiclessuch as cocoa butter and the synthetically produced substitutes thereof,while, for parenteral administration, they may be formulated in ampoulesas injectable solutions or suspensions in sterile liquids, especially inisotonic aqueous solutes.

In the therapeutic compositions in unit dosage form such as tablets,suppositories and injectable ampoules, de rivative (1) or the saltthereof, constituting the active principle, may be present in an amountof about 5 mg. to 1 g. although, generally, a preferred concentrationrange is comprised between about 25 and about 500 mg. in the case oftablets and suppositories.

A daily dosage regimen that was found useful is of 50 mg. to 3 g. ofactive principle by the oral or rectal route, and of 5 mg. to 1 g. bythe parenteral route.

Having now described my invention what I claim as new and wish to secureby Letters Patent is:

1. Therapeutic composition in unit dosage form adapted foradministration to obtain an anti-inflammatory, antipyretic or analgesiceffect, comprising a pharmaceutically acceptable vehicle and from about5 mg. to about 1 g. of an active principle selected from the groupconsisting of a derivative of a 2-amino-oxazolin-4-one of the formulaand a pharmaceutically acceptable acid addition salt of said derivative,wherein R is selected from the group consisting of alkyl containing 1-14carbon atoms, phenyl,

halophenyl, lower alkoxyphenyl and methylene-dioxyphenyl; A is selectedfrom the group consisting of piperazino, C-lower alkyl piperazino andC-di-lower alkyl piperazino; R is substituted on the second nitrogenatom of the piperazino group and is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, N-dialkylaminoalkyl, phenyl,halophenyl, alkylphenyl, alkoxyphenyl, benzyl, alkanoyl, benzoyl,halobenzoylalkyl and trialkoxybenzoyl, said alkyl, alkoxy and alkanoylhaving from 1-6 carbon atoms.

2. Composition as claimed in claim 1, formulated for oral and rectaladministration, containing from about to about 500 mg. of activeprinciple.

3. Composition as claimed in claim 1, formulated for parenteraladministration, containing from about 5 mg. to about 1 g. of activeprinciple together with an injectable liquid vehicle.

4. Composition as claimed in claim 1, wherein said Z-aminooxaZolin-4-one derivative is 5-hexyl-2-N-methylpiperazinooxazolin-4-one.

5. Composition as claimed in claim 1, wherein said Z-aminooxazolin-4-one derivative is 5-phenyl-2-N-propylpiperazinooxazolin-4-one.

6. Composition as claimed in claim 1, wherein said Z-aminooxazolin-4-one derivative is 5-phenyl-2-N-p-tolylpiperazinooxazolin-4-one.

7. Composition as claimed in claim 1, wherein said Z-aminooxazolin-4-one derivative is 5-phenyl-2-N-diethyl- 45 aminoethylpiperazino oxazolin-4-one.

Howell et al.: Journal of Org. Chem., vol. 27, pp. 1679-1685 (1962).

STANLEY I. FRIEDMAN, Primary Examiner US. Cl. X.R.

